CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 2, March/April 2014
84
AFRICA
(7%), compared with glibenclamide (17.9%) and glipizide
(25.6%).
9
Safety data
SUs cause weight gain
2,10
and significantly increase the risk of
hypoglycaemia.
11,12
Hypoglycaemia appears to be associated with
adverse vascular events and death.
13
There are also issues with regard to cardiovascular safety.
There is inconsistency in the results of clinical studies in respect
of SUs and cardiovascular safety. The University Group Diabetes
Program
14
demonstrated increased cardiovascular mortality in
patients treated with tolbutamide. However, the United Kingdom
Prospective Diabetes Study (UKPDS)
4
and the ADVANCE
Collaborative Group
5
did not show an association between
treatment with an SU and adverse cardiovascular outcomes.
In a meta-analysis of 33 studies, with more than a million
study subjects, SU use was associated with a significantly
increased risk of cardiovascular death (relative risk 1.27, 95%
confidence interval 1.18–1.34,
n
=
27 comparisons).
15
Monami
et al
.
16
conducted a meta-analysis of randomised clinical trials
to evaluate the cardiovascular safety of SUs. They concluded
that ‘in type 2 diabetes, the use of sulfonylureas is associated
with increased mortality and a higher risk of stroke, whereas
the overall incidence of major adverse cardiovascular events
(MACE) appears to be unaffected’.
Given the inconsistency of the literature with regard to SUs
and cardiovascular outcomes, a SU cardiovascular outcome
trial is required to clarify the effect of SUs on cardiovascular
outcomes.
16,17
Dose–response relationships
The literature supports the use of SUs at doses lower than the
maximum manufacturer’s recommended dose.
18
Studies have
shown that as the dose of SU is increased, there is initially a
direct relationship between dose and blood glucose-lowering
effect.
18
However, further dose increase results in no further
reduction in blood glucose levels, and, when the dose is further
increased, the glycaemic profile actually worsens.
18
Modified-release formulations have further reduced the
SU dose that is required, compared to the immediate-release
pharmaceutical preparation.
19
For example gliclazide is available
in a modified-release formulation that uses less than half of the
dose of the immediate-release formulation.
19
Cost considerations
SUs remain affordable. This is relevant in countries that have
limited resources and competing healthcare problems. In
sub-Saharan Africa, there are epidemics of not just metabolic
and cardiovascular disease, but also infectious diseases.
20
Tuberculosis and parasitic diseases such as malaria remain
major healthcare challenges, while diabetes, hypertension and
traumatic injuries are increasing.
21
Therefore scarce medical
resources must be distributed to various disease-management
programmes.
However, one may argue that managing SU-induced
hypoglycaemic events (the cost of treating and in some cases the
cost of admission), raises their cost. One may mitigate this added
cost by using the newer SUs that have fewer propensities to cause
hypoglycaemia compared to older agents.
Newer classes of anti-diabetic agents
The ideal anti-diabetic drug should be safe, efficacious and cost
effective. It should not only reduce HbA
1c
levels but also reduce
macro- and microvascular complications. Furthermore, it must
not cause weight gain and hypoglycaemia, and must have durable
efficacy and long-term safety. There is continuing research to
develop newer agents to emulate the characteristics of an ideal
anti-diabetic agent, and therefore better manage type 2 diabetes
patients.
Sodium glucose co-transporter (SGLT) inhibitors and incretin-
based therapies are new classes of anti-diabetic agents. SGLT
inhibitors reduce weight and have fewer propensities to cause
hypoglycaemic events.
22
This is in contrast to the SU class that
increases weight and the number of hypoglycaemic episodes.
Incretin-based therapies include glucagon-like peptide (GLP)
analogues and di-peptidyl dipeptidase IV (DPPIV) inhibitors.
GLP analogues reduce weight but are administered via the
parenteral route. DPPIV inhibitors are weight neutral, have a
low propensity for hypoglycaemia and are administered orally.
The uncertainty surrounding adverse cardiovascular events
associated with therapy with SUs remains,
15
in contrast to the
DPPIV class, which has both meta-analysis
23
and a cardiovascular
outcome trial
24
that demonstrate cardiovascular safety of this new
class.
There are safety concerns with newer anti-diabetic agents.
For example, issues related to pancreatitis and pancreatic
cancer remain with incretin-based therapies.
25
However, the
American Diabetes Association (ADA), European Association
for the Study of Diabetes (EASD) and the International Diabetes
Federation (IDF) have issued a joint statement saying that there
is inadequate information presently to demonstrate a causal
relationship between incretin-based therapy and pancreatitis
and pancreatic cancer.
26
There are also concerns with the SGLT
inhibitor class and bladder and breast malignancies, and urinary
and genital tract infections.
22
The newer agents require further
phase IV data to inform clinical use.
Maximising benefits and minimising adverse
effects of SUs
After considering the adverse effects, safety concerns, efficacy
data and cost, one must use SUs in a manner that maximises
efficacy while limiting the potential for adverse effects. The
question is how does the clinician do this? One way is to choose
the ‘right sulphonylurea, at the right dose, for the right patient’.
The right sulphonyureas: the SUs share a common mode of
action. However, there are differences in pharmacokinetics and
pharmacodynamics between individual SUs. Some SUs have
fewer propensities for hypoglycaemia and weight gain than
others.
27
South African treatment guidelines for type 2 diabetes
specifically mention that glibenclamide must be phased out,
and in the interim it must be dispensed only if renal function is
known.
28
Data derived from the UK General Practice Research
Database (719 general practitioner practices, 34 052 patient-years
of SU therapy) reported that in users of SUs, the annual risk of
